Mice in a scientific experiment. Image from Science Daily.
Science has an interesting read on the frequent disconnect between animal studies and human trials in drug development. Many treatments that look promising in mice models, fail spectacularly in humans. They cite a study on stroke treatments by Malcolm Macloed:
Macleod and his colleagues identified 603 drugs tested in animals, 374 of which had helped heal the brain. Of those, 97 had been tried in humans—and only one had worked. And that one, Macleod is quick to point out, wasn’t tested because of animal data at all, but because it had already benefitted patients with heart attacks.
Currently animal studies have several limitations. For example, in the vast majority of studies animals are not assigned to treatment or control populations randomly. This means that any observed effect might be attributable to something intrinsic to the group and not the drug in question. Additionally, the studies are frequently not blinded, meaning the researchers know throughout the experiment which groups are receiving treatment or a placebo. This tends to introduce bias into studies where researchers observe an effect even that does not exist or overstate its significance. The last problem the article addresses is that many studies use small sample sizes, making the study more likely to observe an effect even when there isn’t one:
What they found was telling. If the two groups [control and treatment] contained just four animals each, there was a 30% chance that an illusory life expectancy gap would show up. With 10 animals per group, the risk dropped to 10%. “You can imagine 10 labs doing this experiment,” says Shai Silberberg, a program director at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland. “One gets an effect, and they publish it.” The other nine are much less likely to submit a paper. Suddenly, the literature is skewed.
The article ends by saying most of these limitations aren’t attempts at obfuscation or intentional misinformation. It also lists some of the steps that researchers and journals are implementing to help improve the current state of affairs. Researchers would like for studies to be more reproducible and translated to humans with greater success. For example the NIH is asking for a 15 question risk of bias assessment be performed for some studies. And journals like Nature are asking for more information on population selection, randomization and blinding with animal study submissions.
The FDA has asked the genetic testing company 23andMe to stop selling its products. The company manufactures over the counter gene testing kits, that allow a user to discover if they have genes that are linked to certain diseases. The FDA says there is little evidence that these kits work. Read the FDA’s letter to 23andMe here.
In the latest edition of Science magazine, two papers describe how bacteria in the stomach and intestines can help improve chemotherapy outcomes – at least in mice.
In the first study, Iida et al. dosed a group of mice with antibiotics for a prolonged period before exposing them to cancer therapies. The antibiotic treatment eliminated their populations of gut microbes. Tumors in these mice did not shrink in response to the therapy as they did in the control group, which received no antibiotics. Similarly, mice brought up in a sterile environment also had showed no chemotherapeutic response. Mice brought up in sterile environments never develop diverse microbial populations since they don’t get exposed to them. Mice lacking the bacterial populations don’t show the production of a protein called tumor necrosis factor that generates the tumor killing response in the organism.
The researchers also found that when the chemotherapeutic drug oxaliplatin was administered to mice who were germ-free or given antibiotics, the cancer killing response was much weaker and ineffective when compared to the control.
The second group of researchers performed similar studies with a chemotherapy drug called cyclophosphamide, or CTX. CTX is used to treat breast cancers and some brain cancers and works by increasing the number of Th17/Th1 immune cells. As in the previously mentioned study, mice that were dosed with antibiotics or that were raised in sterile environments exhibited a weaker anti-tumor response to the CTX.
Results from both of these studies indicate that microbes influence anti-tumor responses. So what does that mean for cancer patients? Dr. Zitvogel, who led one of the research teams, is taking considering the implications saying “We are going to be very careful about prescribing antibiotics during chemotherapy.” Dr. Trinchieri, who led another team, says that we should be cautious about extrapolating any results from mice to humans. He also suggests studies in healthy humans examining the effect of gut bacteria on immune cell production. His sentiment would likely be seconded by most scientists. As a matter of fact, Science magazine has another article in the same issue titled “When Mice Mislead”.
Cesium may bond to fluorine with inner shell electrons at high pressures.
We all learn in introductory chemistry that valence electrons are the only electrons capable of bond formation. But,Scientific American reports on a paper published in the September 23rd issue of Nature Chemistry that predicts that inner shell electrons might form a chemical bond under the right conditions. In the paper, Mao-sheng Miao calculates that at very high pressures (over 30 gigapascals) cesium’s inner electrons will be able to bond to fluorine, forming at least two stable compounds (CsF3 and CsF5).
Cesium, all the way on the left side of the periodic table, has one superfluous electron in its outer, or sixth shell. Fluorine, on the other hand, is toward the far right of the table, just next to the column of noble gases with completely full shells (which is why noble gases are notoriously unreactive—they have little incentive to gain or lose electrons) and is one electron short of a full outer shell. “Under normal pressure, cesium gives an electron completely to fluorine and they bind together,” Miao says. “But under high pressure, the electrons from cesium’s inner shells start to form molecules with fluorine.”
Miao identified two compounds that could form and remain stable up to very high pressures: cesium trifluoride (CsF3), where cesium has shared its one valence electron and two from an inner shell with three fluorine atoms, and cesium pentafluoride (CsF5), where cesium shares its valence electron and four inner-shell electrons to five fluorine atoms.
The article continues, saying that these compounds have yet to be generated in lab thought it should be possible as the require pressures can be generated by modern equipment.
Frederick Sanger, a two time Chemistry Nobel prize winner, died this week at age 95. He was famous for his work sequencing oligonucleotides and proteins. Read about the man and his work at Chemistry Blog.